4,5,6-Trinor-3,7-inter-m-phenylene prostaglandin A1 analogs

ABSTRACT

This invention is a group of 4,5,6-trinor-3,7-inter-m-phenylene prostaglandin-type compounds and processes for making them. These compounds are useful for a variety of pharmacological purposes, including hypotensive control and inhibition of platelet aggregation. 
     A typical formula for a PGA 1  type analog is: ##STR1##

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a continuation-in-part of copending application Ser. No. 677,874 filed Apr. 19, 1976 now abandoned which was a divisional of then co-pending application Serial No. 604,158 filed Aug. 13, 1975 and since abandoned.

BACKGROUND OF THE INVENTION

This invention relates to compositions of matter, and to methods and intermediates for producing them. In particular, the several aspects of this invention relate to novel phenylene analogs of some of the known prostaglandins, i.e. prostaglandin E₁ (PGE₁), prostaglandin F₁α (PGF₁α), and prostaglandin A₁ (PGA₁). The essential material for this application, including the background of the invention, the disclosure of the invention, and the description of the preferred embodiments, including Preparations and Examples, is incorporated by reference from U.S. Pat. No. 4,084,058, issued Apr. 11, 1978, columns 1-65, inclusive, under the provisions of M.P.E.P. 608.01(p).

Previously, certain phenylene-containing prostaglandin analogs were disclosed. See U.S. Pat. Nos. 3,933,897, 3,933,898, and 3,944,595, for a group of phenyleneoxa compounds having a divalent phenylene moiety ##STR2## AND AN OXA OXYGEN (--O--) in the carboxyl-terminated side chain. See Belgian Pat. No. 820,003, Derwent Farmdoc 22475W for related compounds which are distinguishable from prostaglandins in that they are 11-deoxy compounds.

SUMMARY OF THE INVENTION

It is a purpose of this invention to provide novel phenylene prostaglandin analogs and intermediates and processes for making them.

The novel prostaglandin analogs of this invention each have a meta-substituted divalent phenylene moiety ##STR3## IN THE CARBOXYL-TERMINATED SIDE CHAIN OF THE PROSTANOIC ACID STRUCTURE (I). This phenylene group is in place of three of the six methylene portions of said chain.

Included among the novel inter-m-phenylene compounds of this invention are compounds represented by the formulas: ##STR4## and the mixtures of those compounds and their respective enantiomers represented by the mirror images of the above formulas.

In formula VIII, Q is ##STR5## wherein R₃ is hydrogen or alkyl or one to 4 carbon atoms, inclusive; R₁ is hydrogen, alkyl of one to 12 carbon atoms, inclusive, cycloalkyl of 3 to 10 carbon atoms, inclusive aralkyl of 7 to 12 carbon atoms, inclusive, phenyl, or phenyl substituted with one, 2, or 3 chloro or alkyl of one to 4 carbon atoms, inclusive; and R₃₈ is ##STR6## wherein C_(g) H_(2g) is alkylene of one to 9 carbon atoms, inclusive, with one to 5 carbon atoms, inclusive, in the chain between --CR₃₉ R₄₀ -- and terminal methyl, wherein R₃₉ and R₄₀ are hydrogen, alkyl of one to 4 carbon atoms, inclusive, or fluoro, being the same or different, with the proviso that one of R₃₉ and R₄₀ is fluoro only when the other is hydrogen or fluoro and the further proviso that neither R₃₉ nor R₄₀ is fluoro when Z is oxa (--O--); wherein Z represents an oxa atom (--O--) or C_(j) H_(2j) wherein C_(j) H_(2j) is a valence bond or alkylene of one to 9 carbon atoms, inclusive, with one to 6 carbon atoms, inclusive between CR₃₉ R₄₀ -- and the phenyl ring; and wherein L is alkyl of one to 4 carbon atoms, inclusive, fluoro, chloro, trifluoromethyl, or --OR₄₁ -- wherein R₄₁ is alkyl of one to 4 carbon atoms, inclusive, and p is zero, one, 2 or 3, with the proviso that not more than two L's are other than alkyl and when p is 2 or 3 the L's are either the same or different.

There are also included the pharmacologically acceptable salts when R₁ is hydrogen. 

I claim:
 1. An optically active compound of the formula ##STR7## or a mixture comprising that compound and the enantiomer thereof, wherein Q is ##STR8## wherein R₃ is hydrogen or alkyl of one to 4 carbon atoms, inclusive; wherein R₁ is hydrogen, alkyl of one to 12 carbon atoms, inclusive, cycloalkyl of 3 to 10 carbon atoms, inclusive, aralkyl of 7 to 12 carbon atoms, inclusive, phenyl, or phenyl substituted with one, 2, or 3 chloro or alkyl of one to 4 carbon atoms, inclusive; including the pharmacologically acceptable salts thereof when R₁ is hydrogen; wherein R₃₈ is ##STR9## wherein C_(g) H_(2g) is alkylene of one to 9 carbon atoms, inclusive, with one to 5 carbon atoms, inclusive, in the chain between --CR₃₉ R₄₀ -- and terminal methyl, wherein R₃₉ and R₄₀ are hydrogen, alkyl of one to 4 carbon atoms, inclusive, or fluoro, being the same or different, with the proviso that one of R₃₉ and R₄₀ is fluoro only when the other is hydrogen or fluoro.
 2. A compound according to claim 1 wherein Q is ##STR10##
 3. A compound according to claim 1 wherein Q is ##STR11##
 4. A compound according to claim 3 wherein the sum of the number of carbon atoms in R₃, R₃₉, and R₄₀ is less than
 7. 5. A compound according to claim 4 wherein C_(g) H_(2g) is alkylene of one to 5 carbon atoms, inclusive.
 6. A compound according to claim 5 wherein C_(g) H_(2g) is alkylene of 2, 3, or 4 carbon atoms and R₃₉ and R₄₀ are hydrogen, methyl, ethyl, or fluoro, being the same or different.
 7. A compound according to claim 6 wherein C_(g) H_(2g) is trimethylene.
 8. A compound according to claim 7 wherein both R₃₉ and R₄₀ are hydrogen.
 9. A compound according to claim 8 wherein R₃ is hydrogen.
 10. A compound according to claim 9 wherein R₁ is alkyl of one to 12 carbon atoms.
 11. 4,5,6-Trinor-3,7-inter-m-phenylene-PGA₁, methyl ester, a compound according to claim
 10. 12. A compound according to claim 9 wherein R₁ is hydrogen or a pharmacologically acceptable cation.
 13. 4,5,6-Trinor-3,7-inter-m-phenylene-PGA₁, a compound according to claim
 12. 14. A compound according to claim 8 wherein R₃ is methyl.
 15. A compound according to claim 7 wherein one or both of R₃₉ and R₄₀ are methyl.
 16. A compound according to claim 15 wherein R₃ is hydrogen.
 17. A compound according to claim 16 wherein R₁ is alkyl of one to 12 carbon atoms.
 18. A compound according to claim 16 wherein R₁ is hydrogen or a pharmacologically acceptable cation.
 19. 4,5,6-Trinor-3,7-inter-m-phenylene-16-methyl-PGA₁, a compound according to claim
 18. 20. 4,5,6-Trinor-2,7-inter-m-phenylene-16,16-dimethyl-PGA₁, a compound according to claim
 18. 21. A compound according to claim 7 wherein one or both of R₃₉ and R₄₀ are fluoro.
 22. A compound according to claim 21 wherein R₃ is hydrogen.
 23. A compound according to claim 22 wherein R₁ is alkyl of one to 12 carbon atoms.
 24. A compound according to claim 22 wherein R₁ is hydrogen or a pharmacologically acceptable cation.
 25. 4,5,6-Trinor-3,7-inter-m-phenylene-16-fluoro-PGA₁, a compound according to claim
 24. 26. 4,5,6-Trinor-3,7-inter-m-phenylene-16,16-difluoro-PGA₁, a compound according to claim
 24. 